Search for novel physiological function of transcriptional factor Nrf2

• Project/Area Number: 26460354
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Tohoku University
• Principal Investigator: Suzuki Takafumi 東北大学, 医学系研究科, 講師 (70508308)
• Research Collaborator: SEKI Shiori 東北大学, 医学部保健学科, 学生 ; HIRAMOTO Keiichiro 東北大学, 大学院医学系研究科, 大学院生 ; NAGANUMA Eriko 東北大学, 大学院医学系研究科, 技術補助員 ; TAKAHASHI Nobuyuki 東北大学, 大学院薬学系研究科, 准教授 (40588456) ; SATO Hiroshi 東北大学, 大学院薬学系研究科, 教授 (60215829) ; YAMAMOTO Masayuki 東北大学, 大学院医学系研究科, 教授 (50166823)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: Nrf2 / Keap1 / 腎性尿崩症

Outline of Final Research Achievements

Nrf2 regulates the cellular response to oxidative/electrophilic stresses, and loss of Keap1 increases Nrf2 protein level. As Keap1-null mice die of esophageal hyperkeratosis, whole-body phenotypes of Nrf2 hyperactivation in adult animals remain to be delineated. To circumvent this problem, we deleted esophageal Nrf2 in Keap1-null mice. These mice survived until adulthood, but developed polyuria with low osmolality and bilateral hydronephrosis. This novel phenotype appears to be attributable to defects in water reabsorption caused by a reduction in the level of the AQP2 channel in the kidney. This phenotype was recapitulated by renal tubular deletion of Keap1, which generated symptoms of nephrogenic diabetes insipidus, demonstrating that Nrf2 activation in developing tubular cells causes a water reabsorption defect. Our approach to rescue mice from the lethal first hit of Keap1 ablation serves as a useful tool to study novel functions of Nrf2.

Research Products

• [Journal Article] The novel Nrf2 inducer TFM-735 ameliorates experimental autoimmune encephalomyelitis in mice. (2017)
  • Author(s): Higashi C, Kawaji A, Tsuda N, Hayashi M, Saito R, Yagishita Y, Suzuki T, Uruno A, Nakamura M, Nakao K, Furusako S, Yamamoto M.
  • Journal Title: Eur J Pharmacol Volume: 802 Pages: 76-84
  • DOI: 10.1016/j.ejphar.2017.02.044
  • Peer Reviewed / Open Access
• [Journal Article] Hyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus. (2017)
  • Author(s): Suzuki T, Seki S, Hiramoto K, Naganuma E, Kobayashi EH, Yamaoka A, Baird L, Takahashi N, Sato H, Yamamoto M.
  • Journal Title: Nat Commun Volume: 8 Issue: 1 Pages: 14577-14577
  • DOI: 10.1038/ncomms14577
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The aryl hydrocarbon receptor AhR links atopic dermatitis and air pollution via induction of the neurotrophic factor artemin. (2017)
  • Author(s): Hidaka, T., Ogawa, E., Kobayashi, E.H., Suzuki, T., Funayama, R., Nagashima, T., Fujimura, T., Aiba, S., Nakayama, K., Okuyama, R., Yamamoto, M.
  • Journal Title: Nat. Immunol. Volume: 18 Issue: 1 Pages: 64-73
  • DOI: 10.1038/ni.3614
  • Peer Reviewed
• [Journal Article] Absolute Amounts and Status of the Nrf2-Keap1-Cul3 Complex within Cells. (2016)
  • Author(s): Iso T, Suzuki T, Baird L, Yamamoto M.
  • Journal Title: Mol Cell Biol Volume: 36 Issue: 24 Pages: 3100-3112
  • DOI: 10.1128/mcb.00389-16
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Transcription factor Nrf2 hyperactivation in early-phase renal ischemia-reperfusion injury prevents tubular damage progression (2016)
  • Author(s): Nezu M, Souma T, Yu L, Suzuki T, Saigusa D, Ito S, Suzuki N, Yamamoto M.
  • Journal Title: Kidney Int Volume: 91 Issue: 2 Pages: 387
  • DOI: 10.1016/j.kint.2016.08.023
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming (2016)
  • Author(s): Saito T, Ichimura Y, Taguchi K, Suzuki T, Mizushima T, Takagi K, Hirose Y, Nagahashi M, Iso T, Fukutomi T, Ohishi M, Endo K, Uemura T, Nishito Y, Okuda S, Obata M, Kouno T, Imamura R, Tada Y, Obata R, Yasuda D, Takahashi K, Fujimura T, Pi J, Lee MS, Ueno T, Ohe T, Mashino T, Wakai T, Kojima H, Okabe T, Nagano T et al.
  • Journal Title: Nature Commun Volume: 7 Issue: 1 Pages: 12030-12030
  • DOI: 10.1038/ncomms12030
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. (2016)
  • Author(s): Kobayashi EH, Suzuki T, Funayama R, Nagashima T, Hayashi M, Sekine H, Tanaka N, Moriguchi T, Motohashi H, Nakayama K, Yamamoto M.
  • Journal Title: Nat Commun Volume: 7 Issue: 1 Pages: 11624-11624
  • DOI: 10.1038/ncomms11624
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Characterizations of Three Major Cysteine Sensors of Keap1 in Stress Response (2016)
  • Author(s): Saito R, Suzuki T, Hiramoto K, Asami S, Naganuma E, Suda H, Iso T, Yamamoto H, Morita M, Baird L, Furusawa Y, Negishi T, Ichinose M, Yamamoto M.
  • Journal Title: Molecular and Cellular Biology. Volume: 36 Issue: 2 Pages: 271-284
  • DOI: 10.1128/mcb.00868-15
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The subcellular localization and activity of cortactin is regulated by acetylation and interaction with Keap1 (2015)
  • Author(s): Ito A, Shimazu T, Maeda S, Shah AA, Tsunoda T, Iemura S, Natsume T, Suzuki T, Motohashi H, Yamamoto M, Yoshida M.
  • Journal Title: Science Signaling. Volume: 8 Issue: 404 Pages: 404-404
  • DOI: 10.1126/scisignal.aad0667
  • Peer Reviewed / Open Access
• [Journal Article] Molecular basis of the Keap1-Nrf2. (2015)
  • Author(s): Suzuki T, Yamamoto M
  • Journal Title: Free Radic Biol Med. Volume: 88 Pages: 93-100
  • DOI: 10.1016/j.freeradbiomed.2015.06.006
  • Peer Reviewed
• [Journal Article] Myeloid lineage-specific deletion of antioxidant system enhances tumor metastasis. (2014)
  • Author(s): Hiramoto K, Satoh H, Suzuki T, Moriguchi T, Pi J, Shimosegawa T, Yamamoto M.
  • Journal Title: Cancer Prevention Research Volume: 7 Issue: 8 Pages: 835-844
  • DOI: 10.1158/1940-6207.capr-14-0094
  • Peer Reviewed
• [Journal Article] Keap1 inhibition attenuates glomerulosclerosis. (2014)
  • Author(s): Miyazaki Y, Shimizu A, Pastan I, Taguchi K, Naganuma E, Suzuki T, Hosoya T, Yokoo T, Saito A, Miyata T, Yamamoto M, Matsusaka T.
  • Journal Title: Nephrol Dial Transplant Volume: 29 Issue: 4 Pages: 783-791
  • DOI: 10.1093/ndt/gfu002
  • Peer Reviewed / Open Access
• [Presentation] Air pollution activates Aryl hydrocarbon receptor in murine epidermis, leading to Atopic dermatitis-like pathologies. (2016)
  • Author(s): Takanori Hidaka, Eri H Kobayashi, Takafumi Suzuki, and Masayuki Yamamoto.
  • Organizer: The 41st Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: 仙台国際センター(宮城県・仙台市）
  • Year and Date: 2016-12-09
• [Presentation] Air polluteon induces Atopic dermatitiss-like pathologyes via Aryl hydrocarbon receptor (2016)
  • Author(s): 日高高徳、小林枝里、鈴木隆史、山本雅之
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター(宮城県・仙台市）
  • Year and Date: 2016-09-25
• [Presentation] 転写因子Nrf2による炎症性サイトカイン遺伝子の転写阻害 (2016)
  • Author(s): 小林枝里、鈴木隆史、舟山亮、長嶋剛史、中山啓子、山本雅之
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター(宮城県・仙台市）
  • Year and Date: 2016-09-25
• [Presentation] Nrf2活性化は骨形成低下を引き起こす (2016)
  • Author(s): 吉田瑛紀、鈴木隆史、長沼絵理子、小林枝里、守田匡伸、山本雅之
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター(宮城県・仙台市）
  • Year and Date: 2016-09-25
• [Presentation] Keap1センサーシステイン残基による多様なストレス感知機構 (2016)
  • Author(s): 鈴木隆史、山本雅之
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター(宮城県・仙台市）
  • Year and Date: 2016-09-25
  • Invited
• [Presentation] A novel Nrf2 inducer TFM-735 ameliorates experimental autoimmune encephalomyelitis in mice. (2016)
  • Author(s): Higashi C, Hayashi M, Tsuda N, Kawaji A, Nakao K, Satoh F, Nakamura M, Furusako S, Saito R, Suzuki T, Uruno A, Yamamoto M. 
  • Organizer: 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis
  • Place of Presentation: London (United Kingdom)
  • Year and Date: 2016-09-14
  • Int'l Joint Research
• [Presentation] Air pollution activates Aryl hydrocarbon receptor of un-differentiated keratinocytes, leading to Atopic dermatitis-like pathologiesn. (2016)
  • Author(s): Takanori Hidaka, Eri H Kobayashi, Takafumi Suzuki, Masayuki Yamamoto.
  • Organizer: 46th Annual Meeting of the European Society for Dermatological Research. the Technical University of Munich
  • Place of Presentation: Munich (Germany)
  • Year and Date: 2016-09-07
  • Int'l Joint Research
• [Presentation] Keap1の反応性システイン残基による多様なストレス感知機構 (2016)
  • Author(s): 鈴木隆史、山本雅之
  • Organizer: 第69回日本酸化ストレス学会学術集会
  • Place of Presentation: 仙台国際センター(宮城県・仙台市）
  • Year and Date: 2016-08-30
• [Presentation] Characterizations of Three Major Cysteine Sensors of Keap1 in Stress Response. (2016)
  • Author(s): Suzuki T, Saito R, Hiramoto K, Asami S, Naganuma E, Suda H, Iso T, Yamamoto H, Morita M, Baird L, Furusawa Y, Negishi T, Ichinose M, Yamamoto M.
  • Organizer: The 9th International Conference on the Biology, Chemistry, and Therapeutic Applications of Nitric Oxide
  • Place of Presentation: 仙台国際センター(宮城県・仙台市）
  • Year and Date: 2016-05-20
  • Int'l Joint Research / Invited
• [Presentation] 分子構造に基づく転写因子Nuclear factor (erythroid-derived 2)-like 2(Nrf2)の抗酸化剤応答配列認識機構の解析 (2015)
  • Author(s): 鈴木香絵、椎名政昭、浜田恵輔、石川涼平、金井達哉、豊後泰子、岡田千佳子、馬場しほ、鈴木隆史、太田力、山本雅之、緒方一博
  • Organizer: BMB 2015
  • Place of Presentation: 神戸（神戸ポートアイランド）
  • Year and Date: 2015-12-01
• [Presentation] ストレスセンサーKeap1のシステイン変異体ノックインマウスの機能解析 (2015)
  • Author(s): 浅見颯一郎、斎藤良太、平本圭一郎、鈴木隆史、山本雅之
  • Organizer: BMB 2015
  • Place of Presentation: 神戸（神戸ポートアイランド）
  • Year and Date: 2015-12-01
• [Presentation] 新規変異体創出によるストレスセンサーKeap1のシステイン残基の機能解明 (2015)
  • Author(s): 斎藤良太、平本圭一郎、浅見颯一郎、鈴木隆史、山本雅之
  • Organizer: BMB 2015
  • Place of Presentation: 神戸（神戸ポートアイランド）
  • Year and Date: 2015-12-01
• [Presentation] Nrf2欠損マウスにおけるアセトアミノフェン誘発性肝障害の機序検討~ミトコンドリアFusion/Fissionへ及ぼす影響~ (2015)
  • Author(s): 森脇さや香、後藤志麻、宮脇出、出口二郎、船橋斉、鈴木隆史、山本雅之
  • Organizer: 第42回日本毒性学会学術年会
  • Place of Presentation: 金沢（石川県音楽堂、金沢市アートホール、ホテル日航金沢）
  • Year and Date: 2015-06-29
• [Presentation] ストレス応答におけるNrf2, Keap1, Cul3の細胞内分子挙動の解析 (2015)
  • Author(s): 磯達朗, 鈴木隆史, 山本雅之
  • Organizer: 第81回日本生化学会東北支部例会
  • Place of Presentation: 仙台（東北大学さくらホール）
  • Year and Date: 2015-05-09
• [Presentation] Keap1-Nrf2系による生体防御機構 (2015)
  • Author(s): 鈴木隆史
  • Organizer: 第64回脳研・高度先進合同セミナー
  • Place of Presentation: 弘前（弘前大学医学部）
  • Year and Date: 2015-04-23
  • Invited
• [Presentation] Keap1 Cys273 and Cys288 are functional sensors for 15d-PGJ2 to activate Nrf2 signaling. (2015)
  • Author(s): 9.Takafumi Suzuki, Ryota Saito, Kei-ichiro Hiramoto, Tatsuro Iso, Masayuki Yamamoto.
  • Organizer: The Keap1/Nrf2 Pathway in Health and Disease
  • Place of Presentation: Robinson College, Cambridge, UK
  • Year and Date: 2015-01-06 – 2015-01-08
• [Presentation] Multiple Sensor Mechanism of the Keap1-Nrf2 System. (2014)
  • Author(s): 8.Takafumi Suzuki, Kai Takaya, Ryota Saito, Keiichiro Hiramoto, Tatsuro Iso and Masayuki Yamamoto.
  • Organizer: Symposium for young ubiquitin researchers in Japan “New Era in the Ubiquitin Research”
  • Place of Presentation: 京都、国際高等研究所
  • Year and Date: 2014-11-11 – 2014-11-12
• [Presentation] 転写因子Nrf2による炎症性サイトカイン遺伝子の発現抑制 (2014)
  • Author(s): 小林枝里, 鈴木隆史, 舟山亮, 長嶋剛史, 中山啓子, 山本雅之
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都、国立京都国際会館
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] 複合遺伝子欠失レスキュー法による転写因子Nrf2の新規生理機能探索 (2014)
  • Author(s): 鈴木隆史、平本圭一郎、長沼絵理子、高橋信行、佐藤博、山本雅之
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都、国立京都国際会館
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] CRISPR/Cas9システムを用いたNrf2点変異マウスの作製 (2014)
  • Author(s): 守田匡伸、大槻晃史、鈴木隆史、須田博美、鈴木未来子、清水律子、山本雅之
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都、国立京都国際会館
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] 転写因子Nrf2の遺伝子発現量の重要性 (2014)
  • Author(s): 鈴木隆史、柴田龍弘、高屋快、本橋ほづみ、山本雅之
  • Organizer: 日本生化学会東北支部 第80回例会
  • Place of Presentation: 秋田、アキタパークホテル
  • Year and Date: 2014-05-10
• [Remarks] 東北大学大学院医学系研究科 医化学分野
  • URL: http://www.dmbc.med.tohoku.ac.jp/official/index.html